Microelectromechanical system and method for determning temperature and moisture profiles within pharmaceutical packaging

ABSTRACT

A sensor system for determining at least one environmental condition within pharmaceutical packaging comprising a base sheet with at least one pocket formed therein, a lid sheet having a pocket portion, the pocket portion being disposed proximate the pocket when the lid sheet is bonded to the base sheet; and a microelectromechanical (MEMS) sensor disposed proximate the pocket portion.

FIELD OF THE INVENTION

The present invention is directed to devices and systems for sensingenvironmental conditions. More particularly, the invention relates to amicroelectromechanical (MEMS) system and method for determiningtemperature and moisture profiles in pharmaceutical packaging.

BACKGROUND OF THE INVENTION

Pharmaceutical packaging, such as sealed pockets, blister strips, disksand packs, for doses of medicaments or pharmaceutical compositions inthe form of powders, tablets or capsules are well known in the art. Asapplied in dry powder inhaler technology, the pharmaceutical packaging(e.g., blister strips) generally comprise a base having cavities,pockets or open “blisters” adapted to receive a pharmaceuticalcomposition (e.g., inhalable dry powder), a lid that encloses theopening of each cavity or blister, and an adhesive or bonding layerdisposed therebetween to effect a seal.

It is further well known that pharmaceutical compositions, and inparticular, inhaled dry powders, must be maintained in a hermeticenvironment to maintain a high degree of physical stability in particlesize. Only particles having a specific narrow range of aerodynamicdiameter size will deposit in the desired location in the pulmonarysystem. For instance, a particle for local treatment of respiratoryconditions such as asthma will have a particle size of 2-5 μm. Particleto particle agglomeration, shifting the particle size outside of thisrange, will cause the particle(s) to deposit away from the target regionof the lung. Such agglomeration has been associated with moistureingress into the pharmaceutical packaging (i.e., blister). Particlesizes, either in aerodynamic or geometric measures, referred to hereinrelate to a particles effective particle size. Effective particle sizedenotes the apparent particle size of a body without distinction as tothe number of individual particles which go to make up that body, i.e.,no distinction is made between the single particle of given size and anagglomerate of the same size which is composed of finer individualparticles.

Similarly, exposure of a pharmaceutical composition to high temperaturescan, and in many instances will, undermine the stability and, hence,efficacy of the pharmaceutical composition. Accordingly, it is importantto closely monitor the environmental conditions to which apharmaceutical composition is exposed to ensure that the pharmaceuticalcomposition's physical and chemical stability has not been degraded.

Various prior art sensing devices and systems have been employed tomonitor environmental conditions proximate pharmaceutical packagingand/or compositions. However, in general, the noted devices and systemsare not suitable for monitoring environmental conditions “inside”pharmaceutical packaging, and in particular, blister packs.

For example, U.S. Pat. No. 5,739,416 discloses a surface acoustic wave(SAW) device that detects the presence of moisture. Surface acousticwaves are transmitted through a delay path that is attenuated by thepresence of condensation. Unfortunately, SAW devices are extremelysensitive to temperature, pressure, and vibration or other physicalconditions. Compensating for these factors increases the complexity andcost and generally renders SAW sensors unsuitable for use inpharmaceutical packaging.

There are also numerous drawbacks associated with the magnetoacousticsensors disclosed in Jain, et al., “Magnetoacoustic remote querytemperature and humidity sensors” Smart Mater. Struc. 9(2000), pp.502-510. The most significant drawback is that the disclosed sensors aretoo large for incorporation into conventional pharmaceutical packagingand cannot be easily reduced in size, since size reduction substantiallychanges the resonant and interrogation frequencies, as well as theamplitude of the generated signal. Further, the mass changing, moisturesensitive materials disclosed by Jain, et al. would yield unsatisfactoryresults since they do not exhibit enough mass change when incorporatedwith a smaller sensor.

It is therefore an object of the present invention to provide a highlyefficient, cost effective means for determining environmental conditionswithin a multitude of pharmaceutical packaging and, in particular,pharmaceutical packaging having limited internal space.

It is another object of the present invention to provide amicroelectromechanical (MEMS) system and method for determining at leastone, preferably, a plurality of environmental conditions withinpharmaceutical packaging.

It is another object of the present invention to provide a remote sensorsystem and method for determining the temperature profile withinpharmaceutical packaging.

It is another object of the present invention to provide a remote sensorsystem and method for determining the humidity profile withinpharmaceutical packaging.

SUMMARY OF THE INVENTION

In accordance with the above objects and those that will be mentionedand will become apparent below, the sensor system for determining atleast one environmental condition within pharmaceutical packagingcomprises a base sheet having at least one pocket formed therein; a lidsheet having a pocket portion, the pocket portion being disposedproximate the pocket when the lid sheet is bonded to the base sheet; anda microelectromechanical (MEMS) sensor disposed proximate the pocketportion.

The invention also comprises methods for monitoring at least oneenvironmental condition within pharmaceutical packaging. Such methodsinclude the steps of providing at least one MEMS sensor within apackaging assembly, the sensor providing at least a first sensor signalin response to the environmental condition; and determining theenvironmental condition using the first sensor signal. The method mayfurther include the steps of storing the first sensor signal, processingthe first sensor signal using known algorithms and displaying theprocessed information. Preferably, the MEMS sensor is adapted to respondto at least one environmental condition (e.g., temperature), morepreferably, humidity and temperature.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the followingand more particular description of the preferred embodiments of theinvention, as illustrated in the accompanying drawing, and in which likereferenced characters generally refer to the same parts or elementsthroughout the views, and in which:

FIG. 1 is a top plan view of a prior art blister strip;

FIG. 2 is a perspective view of a prior art blister strip;

FIG. 3 is a top plan view of a prior art blister pack;

FIG. 4 a partial section view of a prior art blister containing apharmaceutical composition;

FIG. 5A is a schematic illustration of one embodiment of amicroelectromechanical sensor, according to the invention;

FIG. 5B is a schematic illustration of a microelectromechanical sensormeasurement circuit, according to the invention;

FIG. 6 is a partial section view of one embodiment of amicroelectromechanical sensor system, according to the invention; and

FIG. 7 is a schematic illustration of a further embodiment of amicroelectromechanical sensor system, according to the invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified systems or process parameters as such may, of course, vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments of the invention only, andis not intended to limit the scope of the invention in any manner.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entiretyto the same extent as if each individual publication, patent or patentapplication was specifically and individually indicated to beincorporated by reference.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to “a blister” includes two or more such blisters.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. Although a number of methodsand materials similar or equivalent to those described herein can beused in the practice of the present invention, the preferred materialsand methods are described herein.

In describing the present invention, the following terms will beemployed, and are intended to be defined as indicated below.

Definitions

By the terms “microelectromechanical system” and “MEMS system”, as usedherein, it is meant to mean and include a micro-electronic andmicro-mechanical systems. The systems include a device or sensor havingan integrated circuit combined with a structure that responds to atleast one environmental condition. Preferably, the structure is formedfrom the same material as the integrated circuit using micro-machiningprocessing techniques, such as known integrated circuit fabricationtechniques.

By the term “medicament”, as used herein, is meant to mean and includeany substance (i.e., compound or composition of matter) which, whenadministered to an organism (human or animal) induces a desiredpharmacologic and/or physiologic effect by local and/or systemic action.The term therefore encompasses substances traditionally regarded asactives, drugs and bioactive agents, as well as biopharmaceuticals(e.g., peptides, hormones, nucleic acids, gene constructs, etc.)typically employed to treat diseases and inflammatory and respiratorydisorders (e.g., asthma), including, but not limited to, analgesics,e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine;anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate(e.g., as the sodium salt), ketotifen or nedocromil (e.g., as the sodiumsalt); antiinfectives e.g., cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.,methapyrilene; anti-inflammatories, e.g., beclomethasone (e.g., as thedipropionate ester), fluticasone (e.g., as the propionate ester),flunisolide, budesonide, rofleponide, mometasone (e.g., as the furoateester), ciclesonide, triamcinolone (e.g., as the acetonide), 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester or 6α,9αdifluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester; antitussives, e.g., noscapine;bronchodilators, e.g., albuterol (e.g., as free base or sulphate),salmeterol (e.g., as xinafoate), ephedrine, adrenaline, fenoterol (e.g.,as hydrobromide), formoterol (e.g., as fumarate), isoprenaline,metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g., asacetate), reproterol (e.g., as hydrochloride), rimiterol, terbutaline(e.g., as sulphate), isoetharine, tulobuterol or4-hydroxy-7-[2-[[2-[[3-(2-henylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;PDE4 inhibitors e.g. cilomilast or roflumilast; leukotriene antagonistse.g. montelukast, pranlukast and zafirlukast; adenosine 2a agonists,e.g.,(2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol(e.g., as maleate); α₄ integrin inhibitors, e.g.,(2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino} pentanoyl)amino] propanoic acid (e.g., as free acid orpotassium salt)], diuretics, e.g., amiloride; anticholinergics, e.g.,ipratropium (e.g., as bromide), tiotropium, atropine or oxitropium;ganglionic stimulants, e.g., nicotine; hormones, e.g., cortisone,hydrocortisone or prednisolone; xanthines, e.g., aminophylline, cholinetheophyllinate, lysine theophyllinate or theophylline; therapeuticproteins and peptides, e.g., insulin or glucagon; vaccines, diagnostics,and gene therapies. The noted medicaments may be employed in the form ofsalts, (e.g., as alkali metal or amine salts or as acid addition salts)or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates)to optimize the activity and/or stability of the medicament.

The term “medicament” specifically includes albuterol, salmeterolfluticasone propionate and beclomethasone dipropionate and salts orsolvates thereof e.g., the sulphate of albuterol and the xinafoate ofsalmeterol.

The term “medicament” further includes formulations containingcombinations of active ingredients, including, but not limited to,salbutamol (e.g., as the free base or the sulfate salt) or salmeterol(e.g., as the xinafoate salt) or formoterol (e.g., as the fumarate salt)in combination with an anti-inflammatory steroid such as abeclomethasone ester (e.g., the dipropionate), a fluticasone ester(e.g., the propionate), a furoate ester or budesonide.

By the terms “medicament formulation” and “pharmaceutical composition”,as used herein, it is meant to mean a combination of at least onemedicament and one or more added components or elements, such as an“excipient” or “carrier.” As will be appreciated by one having ordinaryskill in the art, the terms “excipient” and “carrier” generally refer tosubstantially inert materials that are nontoxic and do not interact withother components of the composition in a deleterious manner. Examples ofnormally employed “excipients,” include pharmaceutical grades ofcarbohydrates, including monosaccharides, disaccharides, cyclodextrinsand polysaccharides (e.g., dextrose, sucrose, lactose, raffinose,mannitol, sorbitol, inositol, dextrins and maltodextrins); starch;cellulose; salts (e.g., sodium or calcium phosphates, calcium sulfate,magnesium sulfate); citric acid; tartaric acid; glycine; leucine; highmolecular weight polyethylene glyols (PEG); pluronics; surfactants;lubricants; stearates and their salts or esters (e.g., magnesiumstearate); amino acids; fatty acids; and combinations thereof.

The noted medicaments and excipients may be prepared as compositematerials, such as by co-precipitation or by coating, or other methodknown in the art, or may be prepared from batches of separately preparedindividual particles which are subsequently blended together to formparticulate mixtures of medicament and excipient particles.

By the term “pharmaceutical delivery device”, as used herein, it ismeant to mean a device that is adapted to administer a controlled amountof a composition to a patient, including, but not limited to, theDiskus® device disclosed in U.S. Pat. No. Des. 342,994, U.S. Pat. Nos.5,590,654, 5,860,419, 5,837,630 and 6,032,666. The term “pharmaceuticaldelivery device” further includes the Diskhaler™ device disclosed inU.S. Pat. No. Des 299,066; U.S. Pat. Nos. 4,627,432 and 4,811,731; theRotahaler™ device disclosed in U.S. Pat. No. 4,778,054; the Cyclohaler™device by Norvartis; the Turbohaler™ device by Astra Zeneca; theTwisthaler™ device by Schering Plough; the Handihaler™ device byBoehringer Ingelheim; the Airmax™ device by Baker-Norton; and the Duraand Inhaled Therapeutic active delivery systems. Each of the noted“pharmaceutical delivery devices” are incorporated by reference herein.

By the terms “pharmaceutical packaging” and “packaging”, as used herein,it is meant to mean conventional pharmaceutical containment systems andpackaging having at least one sealable pocket, cavity or blister adaptedto contain at least one medicament or a pharmaceutical composition inany conventional form, including a powder, capsule or tablet. The terms“pharmaceutical packaging” and “packaging” thus include conventionalblister strips, disks (e.g., Rotadisk™), packs, sheets and individualcontainers that are employed in the aforementioned “pharmaceuticaldelivery devices”, including, but not limited to, the pharmaceuticalpackaging disclosed in U.S. Pat. Nos. 6,032,666, 6,155,423 and4,778,054.

As will be appreciated by one having ordinary skill in the art, thepresent invention substantially reduces or eliminates the disadvantagesand drawbacks associated with conventional sensor systems and methodsfor monitoring environmental conditions. As discussed in detail below,the microelectromechanical (MEMS) sensors of the invention can readilybe disposed proximate to or in one or more blisters of a blister strippack, disk or sheet to determine temperature and moisture profilesproximate a pharmaceutical composition sealed therein. The MEMS sensorsof the invention can also be readily incorporated in individualcontainers, such as a vial.

Referring first to FIGS. 1 and 2, there is shown conventionalpharmaceutical packaging in the form of a blister strip 10. Asillustrated in FIGS. 1 and 4, the blister strip 10 includes a lid 11 anda base 14 having a plurality of blisters 12 formed therein adapted toreceive a pharmaceutical composition 13, preferably in the form of a drypowder. Each blister 12 typically has a length in the range of 1.5 to8.0 mm and a width in the range of 1.5 to 8.0 mm. More typically, thewidth is approximately 4.0 mm.

Referring now to FIG. 3, there is shown further prior art pharmaceuticalpackaging in the form of a blister pack 16. The blister pack 16similarly includes a lid (not shown) and a base 17 having a plurality ofblisters 18 formed therein adapted to receive a pharmaceuticalcomposition 13.

According to the invention, the MEMS sensors (and systems) of theinvention are characterized by combining conventional integratedcircuits with mechanical components fabricated from the integratedcircuit materials. As discussed below, in one embodiment, the MEMSsensor includes a polymer coated vapor sensing element that is shearconstrained. According to the invention, the adsorption of water vaporgenerates shear stress that is measured via an embedded strain gauge.The MEMS sensor is also adapted to respond to changes in temperature(e.g., piezoresistive temperature sensing element). Suitable MEMSsensors of this type include the HMX2000™ sensor available fromHygrometrix (Alpine, Calif.).

In the noted embodiment, the vapor sensing element is constructed from athin polymer film deposited and bonded to the top surface of fourcantilever beams that are machined from the surrounding siliconsubstrate using integrated circuit techniques. The shear/stress forcegenerated in the thermoset polymer coating measures the physical van derWaals forces as resistance change. Referring to FIGS. 5A and 5B, aWheatstone Bridge piezoresistor circuit delivers a DC output voltagethat is linearly proportional to relative humidity (“RH”). Furtherdetails of the noted MEMS system are set forth in U.S. Pat. No.5,563,341, which is hereby incorporated by reference in its entirety.

Another suitable MEMS system is disclosed in Wachter, et. al.,“Micromechanical Sensors for Chemical and Physical Measurements”, Rev.Sci. Instrum., 66(6), June 1995. The noted MEMS system comprises arelative humidity sensor that utilizes a micro-cantilever beam with asorption coating of gelatin for measuring humidity. The moisturesensitive coating changes mass as differing amounts of water vapor areadsorbed at different humidity levels. Since the mass affects theresonant frequency of the cantilever beam, measuring the frequencyallows the corresponding humidity to be determined.

Yet another suitable MEMS system is disclosed in U.S. Pat. No.6,128,961, which is hereby incorporated by reference. The noted MEMSsystem relies on the direct integration of a single crystal silicondevice with sensing elements, such as Schottky and junction diodes,piezoresistors, bipolar and MOSFET transistors. The system utilizesmechanical deformation of a sensing element to modulate its electricalproperties.

As will be appreciated by one having ordinary skill in the art, variousadditional, conventional MEMS systems can be employed within the scopeof the invention. Such MEMS systems include the thermo-mechanical sensordisclosed in U.S. Pat. No. 5,917,226 and the MEMS system disclosed inU.S. Pat. No. 6,255,962, which are similarly incorporated by referenceherein.

Referring now to FIG. 6, there is shown a “packaging assembly”,incorporating a MEMS system 20 of the invention. In the noted “packagingassembly” embodiment, at least one MEMS sensor (or system) 21 ispreferably attached to the lid 11 of the pharmaceutical packaging orblister pack 10 prior to sealably bonding the lid 11 to the base 14. Asillustrated in FIG. 5, the sensor 21 includes a lead 21 that extendsoutside the blister pack 10.

Preferably, the sensor 21 is positioned on the lid 11 such that afterbonding the lid 11 to the base 14, the sensor 21 is disposed proximate,preferably, immediately above, the blister 12. In additional envisionedembodiments of the invention, not shown, the sensor 21 is suitablyattached to the base 14 proximate to or within a respective blister 12.

The MEMS sensor is preferably adapted to respond to at least oneenvironmental condition (e.g., temperature), more preferably, aplurality of environmental conditions. Even more preferably, the MEMSsensor is adapted to respond to temperature and humidity (i.e., providesensor signals representative of detected temperature and humiditydata).

Referring now to FIG. 7, in a preferred embodiment, the MEMS system 20further includes a memory 30 in communication with the MEMS sensor 21for storing sensor signals representative of sensed data, a low power,data acquisition processor 32 for processing the sensor signals and adisplay 34.

Preferably, the processor 32 contains the necessary circuitry to amplifyand process sensor signals to a value corresponding to the measuredtemperature, humidity or other environmental condition. According to theinvention, the display 34 may comprise an alphanumeric display thatcommunicates at least stored sensor signals and/or calculated valuesreflecting measured environmental conditions. Alternatively, the display34 may simply comprise an audio or visual indication of whether aparticular threshold condition has been monitored, such as whether theenvironment in the packaging has experienced a predetermined temperatureor humidity.

In additional envisioned embodiments, the circuitry necessary to performthe processing and memory functions of the invention is incorporatedinto the integrated circuitry of the MEMS sensor 21.

The present invention also includes a method for monitoring temperatureand humidity inside pharmaceutical packaging. The method preferablyincludes collecting a plurality of sensor signals representative ofsensed data from at least one MEMS sensor, more preferably, at least aplurality of MEMS sensors, i.e., MEMS 1, MEMS 2. The plurality of MEMSsensors preferably generate sensed data representative of at leasttemperature and/or humidity.

The method also includes converting the plurality of sensor signals intodigital data, processing the digital data, and simultaneously andremotely detecting the processed data to determine the occurrence of atleast one predetermined condition.

The method can also advantageously include remotely communicating theprocessed digital data. The step of remotely communicating the processeddigital data preferably includes transmitting the processed digital databy the use of a RF transmitter and receiving the transmitted RF dataprior to the step of simultaneously and remotely detecting.

The method additionally can include storing the processed digital datauntil remotely accessed, storing the unprocessed digital data untilremotely accessed and displaying processed and unprocessed digital dataafter being remotely accessed, operatively sampling the plurality ofsensors and analyzing the processed digital data at predeterminedscripted real time intervals, and operatively generating a data reportand generating an alarm condition when predetermined thresholdconditions occur.

The method can further advantageously include generating a datacommunications protocol having the processed digital data andcommunicating the data communications protocol having the processeddigital data responsive to remote access.

Without departing from the spirit and scope of this invention, one ofordinary skill can make various changes and modifications to theinvention to adapt it to various usages and conditions. In particular,the invention has been described primarily in reference to thedetermination of temperature and humidity within pharmaceuticalpackaging. However, the invention may be applied to remotely determineany suitable environmental condition within any package, container orother enclosed space. As such, these changes and modifications areproperly, equitably, and intended to be, within the full range ofequivalence of the following claims.

1. A sensor system for determining an environmental condition withinpharmaceutical packaging, comprising: a base sheet having at least onepocket formed therein; a lid sheet, said lid sheet including a pocketportion, said pocket portion being disposed proximate said pocket whensaid lid sheet is bonded to said base sheet; and amicroelectromechanical sensor disposed proximate said pocket portion,said sensor providing at least first sensor signal in response to saidenvironmental condition.
 2. The sensor system of claim 1, wherein saidsensor includes a sensing element having a moisture sensitive coatingthereon.
 3. The sensor system of claim 2, wherein the moisture sensitivecoating changes mass with changes in relative humidity.
 4. The sensorsystem of claim 2, wherein said sensing element comprises a cantileverbeam.
 5. The sensor system of claim 4, wherein said sensing element isshear restrained by said moisture sensitive coating.
 6. The sensorsystem of claim 1, wherein said sensor is further responsive totemperature changes.
 7. The sensor system of claim 1, wherein saidsensor system further includes a memory adapted to receive and storesaid first sensor signal, a processor for determining at least saidenvironmental condition using said first sensor signal and a display. 8.A method for determining an environmental condition withinpharmaceutical packaging having at least one pocket, said methodcomprising the steps of: disposing a first microelectromechanical sensorinto said pharmaceutical packaging pocket, said sensor providing atleast a first sensor signal in response to said environmental condition;determining said environmental condition using said first sensor signal.9. The method of claim 8, wherein said environmental condition comprisestemperature.
 10. The method of claim 8, wherein said environmentalcondition comprises humidity.
 11. The method of claim 8, wherein saidpharmaceutical packaging includes a plurality of pockets.
 12. The methodof claim 11, wherein at least a second microelectromechanical sensor isdisposed in a second pharmaceutical packaging pocket.
 13. The method ofclaim 11, wherein a pharmaceutical composition is disposed in saidpharmaceutical packaging pockets.
 14. The method of claim 13, whereinsaid pharmaceutical composition includes at least one excipient and atleast one medicament.
 15. The method of claim 14, wherein said excipientcomprises lactose.
 16. The method of claim 14, wherein said medicamentis selected from the group consisting of albuterol, salmeterol,fluticasone propionate, beclomethasone dipropionate and salts, solvatesand combinations thereof.